JPS61500915A - New aryl acetic acid derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] New arylacetic acid derivatives The present invention specifically relates to 15-hydroxy-prostabrandin dehydrogenase ( The present invention relates to a novel compound that has an inhibitory effect on PGDH. The present invention It also relates to the production of the novel compounds and pharmaceutical compositions containing them.

The future potential of PGD1 inhibitors as pharmaceuticals remains unclear. Linqiu hasn't come yet. However, in living organisms, gross tag grunge It is well known that prostagland plays a very important role. Any 4% @ that interferes with either the production process or decomposition of gin is a medical X. There is a possibility that it can be obtained by any necessary means. The protective effect of prostaglandins on mackerel cells (cytoprotective effect) in the field of ulcer treatment. Although it is relatively well-regulated, there are still However, the administration of prostaglandins has never been used on a large scale. It was. This is because the administered Brostag 2 in vivo This is because it can only exist for a very short time. Administer prostaglandins Also, drugs that inhibit the breakdown of endogenous grosstaglandin are probably more effective. I don't know if there are any that are very successful.

endogenous prostaglandi ns) #i Inflammation It also plays a major role in inflammatory overpressure. rheumatoid joints Pros in the treatment of inflammation (rheurr + atoid arthritis) It is current practice to use inhibitors of taglandin formation. But by now However, this method is considered to be merely a symptomatic treatment9, and it is on the verge of laughter. It is believed that polar Glostaglandin may still be very effective. Ru. In this sense, the decomposition of grosstaglandin by PGDH is also inhibited. Harm can be very valuable. Furthermore, novelty according to the present invention Prosthetic surgery is a potentially important medical field in which Synv3 can be applied. Grandins interact with the desired controlling factors. All areas that can be treated include circulatory system diseases, cancer, pregnancy, and cellular disorders. There are fields such as industrial production.

Examples of compounds known to have an inhibitory effect on PGDH include European patents. Examples include azo compounds as described in Japanese Publication No. 21229.

These previously used azo compounds have a number of significant drawbacks. The usefulness of these compounds as practical medicines has been diminished due to the fact that emergency A significant drawback is that animals and humans are unable to reduce the metabolic effects of azo compounds. The result is that two aromatic amines are produced. be. This type of metabolism occurs especially in (1) hepatic and tii) hyperphagia, In the large intestine (intestinal microflora) That is, this substance is a friend of the strong reducing conditions created by bacteria that normally live in the intestines. Quality metabolism is promoted.

Due to this kind of substance metabolism, the area of the children to whom it was administered tends to disappear. Direction [6ru. This is already a disadvantage in itself. However, the most important problem is Due to the presence of the above-mentioned aromatic amines, such as aniline, chloroaniline, etc. It is something.

Considering that these amines are formed with 1nViVQ, the azo compound It is not possible to use this product in front-line medical care. very special place Only when the amines formed in vivo make the azo compound active in the treatment It is thought that the toxicity is low enough to permit its use in child The disadvantages of these azo compounds, although to a lesser extent, cannot be ignored. It has a coloring effect, and in the most severe cases it can cause damage to the patient's skin and eyes. This is undesirable as it changes the colors such as KR to such an extent that it is clearly distinguishable from KR. .

OBJECT OF THE INVENTION It is an object of the present invention to provide an improved 7zPGDH inhibitor and a method for producing the same. Dechiru. Furthermore, it is an object of the present invention to provide improved therapeutic methods containing the composition and inhibitors thereof. By providing f.

The new compound has the following formula: [In the formula, & and Tori represent a hydrogen atom or lower alkyl, and preferably Crow represents a hydrogen atom.] death: Bird represents a hydrogen atom, lower alkyl or optionally substituted phenyl; ~ Crows and birds contain hydrogen atoms, halogens, lower alkyl, lower alkoxy, cyano, and carbon. represents ruboxy or nitro, and at least one of the avian groups from R4 is a hydrogen atom From & to bird, hydrogen atom, halogen, cyano, lower alkyl, triph. fluoromethyl, lower alkoxy, hydroxy, lower acyl, lower alkoxyl Bonyl, N, N-di-lower alkyl-aminocarbonyl or FiN, N-lower alkyl Indicates ren-aminocarbonyl, bird to bird. Is it even more difficult to use carboxy? At least two of the atoms 1 are always hydrogen atoms, preferably & and 鰄. Hydrogen atom, halogen, cyanide, lower fulkyl, trifluoromethyl, lower alkyl Oxy, hydroxy or lower acyl: One person - is -co+, -CH -CO-, -0H=C)i-, -C)i=cH-C 〇- or the corresponding group in which the hydrogen atom in the above is substituted with a lower alkyl group ; If a carbonyl group is present, then the ring I'LK of formula [11] Fu is a monster with "Lower alkyl" in the unknown specification and in the Q white of the claim.

The terms ``lower acyl'' and ``lower alkoxy'' preferably contain less than 6 carbons. Indicates a group containing an elementary atom.

The present invention also includes lactones in which KR is a hydrogen atom, and at least one It also includes salts of compounds containing a hydroxy group. Suitable salts are pharmaceutically acceptable and therapeutically active. It has a certain nature.

Suitable salts include metal salts such as sodium, potassium and calcium, or e.g. For example jetanolamine, Trie I'/-#amine, N-methyl-glucamine; Salts with organic amines such as tris-hydroxymethyl-methylamine and the like.

The new compounds of the present invention are almost completely colored, similar to that of azo compounds. T9. It is not metabolized by the body. Therefore, the compound of formula (11) cannot be azotized. There is no drawback of a stiff nose and shoulders. The PGDH inhibitory effect of stiffness compounds has been demonstrated by azo compounds. It's the same or better than that. A major advantage of the uninvented compound is its ability to be absorbed from the gastrointestinal tract. This means that the compound contains groups that differ significantly between them. I'll list it.

The present invention has systemic effects that are rapidly and completely absorbed into the bloodstream. Contains compounds with excellent rounding properties. On the other hand, other compounds are absorbed Some forms of the Tsumashi method (1) are less susceptible to being wired into the gastrointestinal tract. The compound can be used to treat gastric conditions such as back ulcers, localized ileitis (Crohn's disease), and ulcerative colitis. This means that it can have the ability to locally act on diseases of the intestinal tract.

The compounds of the invention may be prepared by various combinations of methods known per se. . In general overview, these methods can be categorized into six different general types. Ru. There are a certain number of methods selected in the manufacture of wafers, such as two or more rigs. It is a combination of common types of methods.

General type prisoner The first general type person is the following formula [In the formula, indicates a group that can be substituted by XI-jOH, from bird to bird.

and one can treat the compound of formula 11>l with the same meaning as in formula 11 to convert X to 0HKtl t exchange. Examples of the X group are amino, nitro, lower alkoxy, allyloxy, Lower acyloxy, aryloxy, lower alkylsulfonyloxy or aryl Rusulfonyloxy is present. When X is lower alkoxy, the reaction is performed using a strong acid reagent example. For example, sulfuric acid (9) can be prepared by a strong mineral acid such as hydrobromic acid, optionally in the presence of water. This is done by processing the K, aluminum chloride, tribromide using strong acids The reaction may be carried out in the presence of a Lewis acid such as boron.

When x6=7lyloxy, the reaction is done in the same way as when X is alkoxy. or by isomerizing the double polymer, preferably in the presence of water in an acidic medium. A method of forming a propenyl rust conductor and rapidly hydrolyzing it in the acidic medium. This isomerization reaction is performed using gold such as palladium or platinum. By treating with a catalytic converter, continuous recovery can be achieved. X is lower acyloxy, aryl In the case of oxy, lower alkylsulfonyloxy or arylsulfonyloxy The 0I-IK diSi donor reaction is preferably carried out in water or in an active medium containing water mixed with water. It is carried out by alkaline hydrolysis at . After the reaction is complete, the resulting reaction mixture neutralize.

When X is NH, the diazonium salt is diazotized and then subjected to conventional hydrolysis. The reaction is most preferably carried out by doing this.

When X is NO, the NOx group is first reduced to amino and then the above-mentioned The amino group of sea urchin is converted to 0)IK[.

General type B The second general type is the following formula %formula% [In the formula, Y represents a group that can be substituted with -C Uma R3000Bq, and from Karasu to Uma 1 and Human is treated with the compound I] having the same meaning as in formula (1) to convert Y to 10R,R,- Replace with 000R,r.

YC1f! #iH, -0R5-CN, CRaR5CH=CH*.

-Co-COO1'L (R is lower alkyl), -0(sa) bird-COO horse t( R and bird! is hydrogen or lower alkyl), -c(oR)2-cth x, -by( R is lower alkyl and X is iodine, alkylsulfonyloxy or aryls Ruphonyl, oxy) causes a chill.

Y is H (0191, reaction FI Xz Cr1dLz-COORI (Xs is O This is accomplished by upkylation using H or halogens. What if? When is a halogen, the reaction is carried out under alkaline conditions to form an 0-alkylated product. 6 to maximize the yield of the C-alkylated product. Preferably the reaction is Under anhydrous conditions: Ct.

It is carried out in the presence of a Lewis acid such as 5nO44 or Tiat. X, is 0H ( 7) If ICrX, (a>R, and - are both lower alkyl or tb) In the phenyl with Ra, which one is hydrogen atom or lower alkyl) - When the reaction temperature is 66° and OH is required, the reaction is preferably carried out using, for example, sulfuric acid. It is carried out in the presence of minerals such as ν.

When Y is -C R, -ON, the reaction is carried out by methods known per se, It is carried out by caustic or caustic hydrolysis.

When X is C-~-〇)l=OH, the reaction is e.g. If kept, transition metal oxidation, Bottle n04 or Cra,) or metaperiodine related salts, Also, for example, oxidation using 0s04 or Shame04 as a catalyst is performed. Ru.

If Y is 10 (SR) R, -Coo, for example, Raney nickel or zinc The reaction is carried out by reduction treatment using in an acidic medium.

If Y is -c(on, +1-G It is carried out in the presence of a weak base for summing. If X is iodine, peracid It is useful to carry out the reaction by oxidizing with compounds or other oxidizing agents such as chlorine. It is advantageous.

If Y is 100-COOR, the reaction may include, for example, catalytic reduction and hydrogenation. This is done by decomposition.

General type C The third general type, C, is the formula [In the formula, birds and humans have the same meaning as in 11, and from bird to genus, at least one of the groups is not identical to the corresponding group in RHO from the horse and is removed by chemical reaction. The same as the equation (11 horse to horse, 7 which has the same meaning It is characterized by using a compound of

When the bird is a hydrogen atom, the conversion to a compound where the 狋 and 八 are lower alkyl is as follows. This is carried out by alkylation by methods known per se. Melon, melon and bird are hydrogen atoms , cyano, hydroxy or amino, and at least two of them are hydrogen atoms If selected to be a child, the compound has the correspondence given by formula +11. It can be converted into a compound by a halogenation reaction according to known methods. R,, If the horse or chicken is cyano, this group can be hydrolyzed by methods known per se. can be converted to carboxy (OOOH). One or two of the following four When the group is hydroxy, these can be obtained by alkylation by methods known per se. can be converted to alkoxy. If the melon, chicken, or chicken is an amine, it is itself public. diazotized by known methods and subsequently reacted with halogen salts or cyanide salts. Therefore, it can be converted to halogen or cyano.

Similarly, Peng to Trap also follows a reaction pattern that is known per se and corresponds to the method described above. can be converted from new & to Rlt.

General type D The fourth one rainbow type, D is the following formula [In the formula, Rstf': I has the same meaning as in formula (1), and X is It is also characterized in that it uses a compound of j] which is a group that can be converted into the corresponding group AK. It is. For example, C(OR)t-1-cRx, -co-9-OR(OH) -'Sa-, -〇)LFL-OH(OH)--OH, -0FLX, -Co- raυ, B is halogen or lower alkyl.

indicates OH, halogen or esterified alcoholic OH.

When X is 10 (OR), -, the reaction Fi is carried out by acidic hydrolysis and the crosslinking -C O- forms.

When X is 10RX, -co-, reductive hydrogenolysis, preferably specific to the C-bond The reaction can be carried out by conventional catalytic hydrogenation.

A'$ -0R(0)1) -CHz -, -C肚-0H(OH)- or -QH ,-C! RX.

In the case of -CO-, H20 or FiHX is removed by treatment with an acid or alkaline reagent, for example. By doing so, a reaction is carried out.

General type E The fifth revision type, E is the following formula [In the formula, & has the same meaning as in formula (1)] and the following formula [In the formula, from bird to R, have the same meanings as in formula (1)] By reacting in such a way that 4 and 4 react with each other to form one group per person. It is characterized by Examples of combinations of Y4 and Y4 include the following.

-CO-X, and H or, respectively, H and -C! 0-XI (XI is OH or H -CHt-Co-X, and H; -cR=p(c,H,)m and HCO - or -COR and ((sHm　)m P=CH-nee CHO and 几-OH, - Co.

If the reactions are similar to acylation reactions, these reactions can be carried out using the appropriate #1 reaction. =, pg media and reagents such as tc4, 5nC4, 'I'iC4 or BF, etc. It must be done in the presence of something.

To form -0H=O-CO- from -0HO and R-CHt-Co-, The reaction may be carried out, for example, by using an acidic or alkaline catalyst in the presence of a solvent. Not get. -0B-P (0sHi)s and HCO-1 or -COR and (C , ) (live), P=CB- to -0R=O) (known per se to form - The reaction is carried out in a method.

General type F The sixth general type, P converts the compound of formula (1) into the corresponding lactone of the formula or convert the lactone 2^1 into the compound of formula (1), or convert P4 to another compound. It is characterized by changing into another crow.

When & is a halogen, by a simple method using modified ri acid to form a lactone, If desired, a dehydrating reagent such as acetic anhydride or thionichloride A/, or e.g. It is carried out under other conditions, such as co-gripping, where water is removed from the urine. bird is lower alkyl In this case, the reaction is carried out with a base, but the lactone produced is hydrated with the corresponding acid. Perform alms while being careful not to disintegrate.

The lactone of the present invention is produced by hydrolysis with alkali and subsequent a<fR conversion. It can be readily converted to the corresponding acid. or in the presence of a basic catalyst such as a mineral acid. It can be converted to the corresponding ester by treatment with the corresponding alcohol.

If the island is a hydrogen cylinder, the compound can be subjected to an esterification reaction by a method known per se. Thus, it can be converted to the corresponding ester where avian is lower alkyl.

When the compound is lower alkyl, the compound is alkaline hydrated by a method known per se. It can be converted to the corresponding acid by decomposition and subsequent acidification.

In producing the compounds of the present invention, two of the methods belonging to a series of general types λ to F are used. Combine two or more reactions simultaneously or one after the other without isolating intermediate products. Significant advantages can often be obtained by following this in direct succession. Wear. For example, it is often advantageous to react as follows.

The following compounds The following compounds [In the formula, R and R represent lower alkyl, preferably methyl; 1) React with 1] having the same meaning as inside under the activity of excess ebts to form acylation. At the same time or immediately after and/or during work-up to cleave the R and he groups. This reaction is applicable to, for example, the following compounds or The corresponding lactate is a compound with very low reactivity during the reaction. yields higher than those obtained when performing the same type of reaction using can be done.

bird R1 As another example of simultaneous reaction, the following compound [wherein Ru and Karasu are (1)] has the same meaning as, R is lower alkyl, one group from melon to horse 1 is hydrolyzable groups such as cyanide, carboxylic esters or carboxylic amides. 7 to represent something It's something that converts.

Said hydrolyzable groups selected from among gourds to traps can be treated with strong mineral acids. and at the same time, R and & are optionally placed on the hydrogen atom. will be replaced.

Yet another example is the formation of lactones simultaneously with the hydrolysis of hydrolyzable groups. There are things that can be done. A number of such combinations are detailed in the many central legends below. nru.

At least one play g7! Compounds of the present invention containing a carboxy group are suitable for the compound. in the presence of a solvent, such as sodium hydroxide, potassium hydroxide or a suitable A suitable salt-forming reagent such as a suitable organic amine can be readily converted into the corresponding salt by reacting with the agent).

The salt can be prepared as a solid by removing the solvent by methods known per se, or directly in the bath liquid (if it can be dissolved), preferably in that form directly in the water bath liquid. Prepared for use.

The novel pharmaceutical compositions of the present invention contain a therapeutically effective amount of a compound of formula (1) or a lactate thereof. ;/or a salt of the compound containing at least one carboxy 7 group, as desired. For oral, rectal or parenteral administration, they are sterilized and/or further adjuvanted. 〇 [The composition is prepared by methods known to those in the clam industry. Combining the active substance with the base substance Optionally, further mix with an adjuvant and fill the resulting mixture with a precipitated galenic form ( galenic form). For dosage, please refer to people weighing 75 breasts. ◇According to the present invention The new formulation for popHmy provides therapeutically effective doses of the formula to mammals, including humans. (+1 compounds, lactones thereof or compounds containing at least one carboxy 7 group) comprising administering a pharmaceutical composition comprising a salt of the compound.

The following examples serve to explain the invention in detail without limiting the scope of the invention. .

lol million cases 1 (a) 2-methoxybenzene 2-methoxybenzene acetic acid 500 Dissolve g in 4 L of methanol and 150 − of sulfuric acid (d=L84). This bath liquid is 2 Boil for 4 hours and then pour over ice water. Extract the aqueous phase with chloroform and combine with water and Shake to mix against sodium bicarbonate, then evaporate this chloroform solution. make it emit

99 is dissolved in 65 rJ of methylene chloride. aluminum chloride for 20 minutes. 25 g of aluminum are added in portions under reflux. Boil this mixture for 22 hours in a well. After returning to 0 temperature, it is poured onto water and extracted with about 300 ml of ether. steaming The residue after image development was mixed with 200t of 1M sodium hydroxide/200t of ethanol. Boil for hours to hydrolyze. This state is adjusted to 8 using concentrated hydrochloric acid. Activated charcoal After treatment and filtration, the solution was heated to about 70°C and diluted with hydrochloric acid to about 3. to precipitate the product. After cooling, the product is taken from house to house, rinsed with water and dried.

NMR spectra and elemental analysis data are consistent with the structure of the title compound. The melting point is It would be 205℃ Example 2 (a) Methyl-2-hydroxy-benzene acetate vinegar 82-hydroxy-benzene 250 g of 1c24 hr. Boil for a while. Pour this solution onto ice water and extract with chloroform. This chlorophore Shake the lume solution against the sodium bicarbonate and water solution, then mix with a sulfuric acid mug. Dehydrate with nesium. This solution was evaporated, the residue was dissolved in methylene chloride and activated charcoal was added. Process with. Add 4 Q Owt of petroleum ether to this solution with gentle heating. The bath liquid is cooled to -20°C, and the crystals are then separated and washed with petroleum ether.

(b) 5-benzoyl-2-hydroxy-benzene = S methyl-2-hydroxy -Benzene acetate-) IL6g and benzoyl chloride 149 to nitrobenzene xoo *Understand K11G. Heat for about 10 minutes and add aluminum chloride 279 slightly. -Stir the solution at 60°C for 24 hours. After cooling, place it on ice water and hydrochloric acid. pour. This mixture is extracted with chloroform and the chloroform phase is steam distilled. steaming The residue was leached with hot water, dissolved in chloroporm, and then added to a sodium bicarbonate solution. Shake to mix. Evaporate the chloroform phase and dissolve the residue in sodium hydroxide. Boil for 1 hour in 100ml of water containing 2g. Add 100% of methanol to this hot solution. and acidify it with formic acid. After cooling, the product is oven dried.

NMR spectra and elemental analysis data are consistent with the structure of the title compound. The melting point is The temperature is 205°C.

Example 3 λ5-dimethylbenzoin+ff159. Chloroform zoow, thionyl chloride l〇 - and dimethylformamide IMt until no more) 1 ct is generated. Boil. This solution was concentrated and methyl-2-methoxy-benzene acetate 169 and nitrobenzene 100-. aluminum chloride over 15 minutes Add 9 g in portions and maintain the flask at approximately 55° C. for 18 hours. This solution Pour onto water-cooled hydrochloric acid and extract with chloroform.

This chloroform phase was washed with water and steam distilled, and the residue was extracted with 1M sodium hydroxide. It is hydrolyzed in 00- and ethanol 20-g. - to about 7 and add this solution to Mix by shaking against chloroform. After evaporating and concentrating this and cooling, 2&5g of crystals Obtain deposits. The crystals were dissolved in 100% of ethanol and 400% of water, and acetic acid was added. When added, the title acid crystallizes.

NMR spectrum and elemental analysis data are consistent with the structure of the title compound.

(b) 5-3.5-dimethyl-benzoyl-2-hydroxy-benzene vinegar acid 5-(λ5-dimethylbenzoyl)-2-methoxy-benzeneacetic acid 10 g, beauty Hydrohydric acid (40 w/v% in acetic acid) 40-.

Water 15- and hydroiodic acid 2- are refluxed for 24 hours. After cooling, pour this solution over water. Pour into. The precipitate was taken from house to house and boiled in 100Nt of 2M sodium hydroxide solution. Dilute this with 600ml of water and #100 of ethanol. Adjust your voice to about 7 and use this Treat the solution with activated carbon and heat to its boiling point. Add acetic acid. The crystals precipitated from the solution. The crystals are taken one by one, dissolved in acetic acid, and treated with activated carbon. Adding water to this solution causes the product to condense. crystallize. This is recrystallized from acetic acid.

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. The melting point is The temperature is 242°C.

Example 4 19.6 g of 4-(2-722-1-ethenyl/l/)-phenol.

Water separation of 146 g of benzene boronic acid, 18 g of propionic acid and 100 g of toluene Reflux using a container.

12.0 g of rose formaldehyde is added in portions over a period of 5 hours. This mixture Let things boil for another hour. After cooling to room temperature, add ether 100- and crystallize. The resulting product is washed with ether.

− Make U work hard. Add 325 grams of hydrogen peroxide at 30% W/W for about 10 minutes. Add portionwise while stirring and cool to room temperature.

The reaction mixture was allowed to stand for 20 minutes and then poured onto ice water, after which the precipitated product formed was Wash each door with water.

(c) 2-Hydroxy-5-2-phenyl-1-ethynyl 2-Hydroxy-5-(2-)mo-1-ethynyl)-benzene methanol 9 ．． 19 and potassium cyanide &15g in dimethylformamide 120-24 Heat at 120'C for an hour. Add 20 grams of water and adjust to about 101C with sodium hydroxide. make a clause This solution is evaporated to dryness. Dissolve the residue in 50°C of water. Add this solution to acetic acid Neutralize with water and extract several times with ether. After washing several times with water, this ether phase was evaporated to dryness. let

The residue is hydrolyzed by boiling for 6 hours in 10 - of water and 7 - of #C sulfuric acid. this The solution is diluted with water and extracted with ether. Extract again with alkyl. After drying and concentration, The resulting compound was reprecipitated from an alkali using an acid, and then made from oak, and then mixed with acetone and Recrystallized from petroleum ether NMRM spectra and fractional analysis data are consistent with the structure of the title compound. melting point is 202°C.

Example 5 2-Hydroxy-5-(4-crocobenzoyl)-benzeneacetic acid 4-Cucoropenzoy chloride 17.59 and methyl 2-hydroxypene Zenacetego÷itrobenzene 10 ()iK dissolve. Salt for about 20 minutes Add aluminum 279 little by little. The solution was maintained at 60°C for 16 hours, Then pour over glacial hydrochloric acid. This mixture was extracted with chloroform, and the chloroform The phase is steam distilled. The distillation residue was dissolved in chloroform, treated with activated carbon, and dissolved in hydrogen carbonate. Shake to mix 1:1 in the thorium solution. Evaporate the chloroform solution and leave the remaining The oil was mixed with petroleum ether-benzene and the resulting crystals were separated. this crystal Boil it in 100ml of water containing 4g of sodium hydroxide for 1 hour to decompose the skin water and remove hydrochloric acid. Add dropwise until crystals begin to precipitate. The melting point of the product after discarding is 250°C.

Example 6 5-4-cyanobenzoyl)-2-hydroxy-benzene vinegar 4-Schiff/An 14g of zoic acid, 100g of chloroform, 10g of thionyl chloride and dimethylform. Boil Muamido o, 25 go for 6 hours. Evaporate this solution and nitrate the residue. Dissolved in lobenzene 100rILt, methyl 2-hydroxy-benzene acetate -) Add aluminum chloride 409 for about 20 minutes. Add one. The solution is kept at 50° C. for 8 hours and then poured onto glacial hydrochloric acid. child The mixture is extracted with ether and the ether phase is evaporated. steam this oil The residue was extracted with chloroform, and the chloroform solution was then distilled with sulfuric acid. Dehydrate with magnesium acid and treat with activated carbon. Evaporate this chloroform solution and Dissolve the slag in ethanol at about 50 + dK and add it to 100 - dK potassium hydroxide bath solution. Splits water. The resulting solution is 0.5! , and acidify with formic acid. The product is It crystallizes and is dried from door to door.

The NM spectrum and elemental analysis data are consistent with the design of the title compound. melting point The temperature is 1218°C.

Laughing example 7 2-hi)"E:I'l"-5-4-carboxybenzoyl-benze5-(4- cyanobenzoyl)-2-hydroxy-benzeneacetic acid 29, acid 920d, water 10 - and boil in sulfuric acid for 24 hours. Cool the solution to room temperature. precipitation Go door to door and wash it with water. This precipitate was boiled in 1M potassium hydroxide solution for 18 hours. let The solution is acidified with formic acid and cooled. The product thus crystallized is separated into furnaces. Wash with water and dry.

NMRM spectra and cumulative analysis data are consistent with the structure of the title compound. melting point The temperature is as high as 260℃.

Example 8 4-cyanobenzoic acid 10, thionyl chloride 8, dimethylformamide 0.5- and chloroform 100- are boiled for 16 hours and then evaporated.

35g of aluminum chloride and 80ss of nitrobenzene! Dissolve in. This acid chloride and methyl 2-methoxybenzeneyl chloride 17-29 Add 0-nitrobenzene. This solution was maintained at 60°C for 24 hours, then The mixture was poured onto ice water and extracted with methylene chloride. This methylene chloride phase is diluted with hydrochloric acid and Mix by shaking against water. This is concentrated and diluted with petroleum ether. crystal door Separate and recrystallize from ethanol.

Methyl 15-(4-cyanobenzoyl)-2-methoxy-benzene acetate 1 0 g to 40% W/W hydrogen bromide (in acetic acid) Rood, water 30- and hydrogen iodide 2I Boil in ILt for 24 hours. Pour this solution over water, separate the precipitate, and soak the mother liquor in vinegar. Extract with ethyl acetate, evaporate and pool together with the precipitate. The product was treated with α5M hydroxyl for 30 minutes. ≠ was adjusted to about 6 with acetic acid, and the solution was treated with activated carbon. Understand. This was then heated to about 70°C, and formic acid was added to begin crystallizing the product. The solution is then cooled. The product is washed and dried separately.

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point Example 9 5-benzoy A/-3-promo 2-hydroxy-benzeneacetic acid 5-benzoy 13-2-hydroxy-benzeneacetic acid and 5 g of sodium acetate were added to tetrahydrochloride. Dissolve Ro7 Run 15011ItK.

1 (l) of bromine dissolved in 50 wtK of tetrahydro7ran was added dropwise to this solution over a period of about 1 hour. down. The solution is evaporated and the residue is then dissolved in a small amount of methanol. this Acidify the methanol solution layer with sulfuric acid and distribute it from house to house. This bath part was heated with 150d of methanol. Dilute.

20 ml of sulfuric acid is added and the solution is then boiled for 18 hours.

This was poured onto ice water, extracted with benzene, and recrystallized from benzene-in-octane. This product was recrystallized twice from methanol-water to IM sodium hydrate. Hydrolyzes in solution. The resulting solution was acidified with hydrochloric acid, extracted with chloroform, Dehydrate with magnesium sulfate and evaporate. Recrystallize the residue from benzene-isooctane to become Dry the product from house to house.

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is 132°C, Example 10 2-7 k O* AnJliFR14g, chloroform loat, [chemical Boil 10m of onyl and dimethylformamide 1- for 6 hours. 18g and dimethylformamide. 50 g of tyrene, and the mixture was mixed with methyl chloride containing 50 g of aluminum chloride. The mixture was poured into a glass of water and boiled for 6 hours. Pour this solution into ice water poured on top, extracted with chloroform, dehydrated with magnesium sulfate, and treated with activated carbon. d The residue is recrystallized from benzene-isooctane. hydroxylate the product ) Hydrolyze in IJum 300g and acidify the hot solution with acetic acid. Living Once the product begins to crystallize, the solution is cooled and the product is distributed.

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is 102°C.

Example 11 5-λ+-dichlorobenzoyl-2-hydroxy-benzeneacetic acid This synthesis is carried out in the same manner as in Example 1O. ◇NMR spectrum and elemental analysis The data are consistent with the structure of the title compound. The melting point is 226°C.

Example 12 This synthesis is carried out in the same manner as in Example 10.

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is 171°C.

Example 13 5-benzoyl-2-hydroxy-3-chloro-benzene methyl acetate 5-benzo IL39. N-chlorosuccinid 7 g of S and 10011/ml of chloroform are boiled for 18 hours'a. Steam this suspension. Emit, dissolve in benzene and shake against water to mix. Dry evaporation of benzene solution Slow down. The residue is also recrystallized from benzene-isooctane 711).

The product was boiled in sodium hydroxide for 1 hour;

The solution obtained is acidified with hydrochloric acid. This solution is then cooled and the product is distributed door to door. and dry. NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is 131°C.

Example 14 Methyl 2-hydroxy-benzene acetate 1a6g and phenylacetyl Dissolve 4 g of 2D IL in 100 g of nitrobenzene. Aluminum chloride at room temperature Moum 279 is added in portions and the solution is then maintained at 60° C. for 8 hours. after that This is poured onto glacial hydrochloric acid and extracted with chloroform. Steam this chloroform solution Distill and the residue is water split in boiling sodium hydroxide. -i7 to v4 clause The solution is extracted with chloroform.

The aqueous phase is acidified with hydrochloric acid, and the resulting crystals are then dried door to door.This product is Recrystallize from tilketone-chloroform.

NMR spectra and elemental analysis data are consistent with the structure of the title compound. melting point Chill at 198℃.

Example 15 (,) Methyl 5-(2-(4-cyanophenyl)-acetyl)-2-methoxy seabenzene acetate 4-cyano-benzeneacetic acid 1&29. Thionyl chloride 12g.

Boil chloroform 100- and dimethylformamide α511tt for 4 hours. Ru. The solution was evaporated and the residue was purified with methi/I/-2-methoxy-benzene acetate. Solve methylene chloride soyKm containing 2α3g. This solution contains 60sd of lead chloride. Add dropwise to a 250% methylene chloride solution. Boil this solution for 18 hours, Pour onto ice water and extract with chloroform. This chloroform phase is mixed with magnesium sulfate. Dehydrated, treated with activated carbon and evaporated. The residue is recrystallized twice from ethanol.

(b) 2-hydroxy-5-(2-(4-carboxyphenyl)-acety/I/ )-benzeneacetic acid Its melting point is higher than 260°C.

Example 16 36 g of methyl 2-methoxy-benzene acetate and acetyl chloride 1 & 79 are salted. Dissolve 100% of methylene chloride in the resulting solution containing 100% of aluminum chloride. Add dropwise to 300 methylene chloride. This solution was left to stand for 3 hours for 5 hours, and then poured over ice water. do.

Cleaning the crystals with water and methylene chloride (b) 5-(3-)dinyl-1-oxo-2-propenyl)-2-hydroxy- benzene acetic acid Methyl 5-7ceteru-2-hydroxy-benzene acetate lα<9. benzua 5.3 g of aldehyde, 5M sodium hydroxide and ethanol/l 15011I This solution is stirred in an ice bath for 4 hours and then for 20 hours at room temperature. Dilute with 150 g of water and add acetic acid dropwise.

Dry the precipitate door to door. This was recrystallized with ethyl methyl ketorebenzene. dry.

The NMR spectrum and elemental analysis data are consistent with the four-form structure of the compound. melting point Chilled at 198°C Example 17 2-hydroxy-5-3-4-carboxyphenyl-1-oxo-2-prope The main synthesis of nyl-benzene was carried out in the same manner as in Example 1s [b). Lamb and elemental analysis data are consistent with the structure of the title compound. Melting point is around 260℃ expensive.

Example 18 147 g of 3-cyanobenzoic acid, 40 d of chloroform, 10- and di-thionyl chloride Boil methylformamide α2- for 18 hours.

This solution was concentrated and then methi/l/2-methoxy-benzene acetate)7.39 and methylene chloride 20-. The resulting solution was dissolved in 10Qd methylene chloride. Add to the solution of 24 - of tin chloride and boil the whole for 48 hours. Pour this bath solution onto ice water. extracted with chloroform, treated with activated carbon, evaporated, and the residue was dissolved in a small amount of ethanol. and recrystallize from methanol-water.

The synthesis is carried out as in Example 8 and F3.

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. melting point is higher than 260°C.

Example 19 Methyl 2-hydroxy-5-(2-/+30 pence/L/)-benzeneacetate root 2-chlorobenzoic acid 15.69. Thionyl chloride 10-2 melene chloride 150m g and dimethylformamide Q, 5a! Boil until the generation of hydrogen chloride gas stops. Ru. The solution was evaporated and the residue was dissolved in methoxy, It/-2-methoxy-benzene acetate. -) 189 in methylene chloride containing 50-. Add this solution to aluminum chloride The mixture was added dropwise to 200 g of methylene chloride containing 509 and boiled for 16 hours. Put this solution on ice. Pour over water, extract with chloroform, dry and treat with activated charcoal. then evaporate The residue is dissolved in benzene-petroleum ether and treated with activated carbon. Add petroleum ether O to precipitate crystals The NMR spectrum and elemental analysis data are consistent with the 4 structure of the title compound. melting point is 119°C.

Example 20 Methyl-5-(4-fluorobenzoyl)-2-hydroxy-benzene acetate to This synthesis is carried out in the same manner as in Example 19.

NMR and elemental analysis data are consistent with the structure of the title compound.

The touch point is 173°C.

Example 21 s-(4-fluorobenzoyl)-2-hydroxy-benzeneacetic acid Methyl 5-(4-fluoropency/I/)-2-hydroxy-benzeneacetic acid T) 15g in α5M sodium hydroxide 300d and ethanol 10-15g Boil for a minute. - is adjusted to about 7 with hydrochloric acid and the hot solution is acidified with acetic acid.

Cool this solution to about 40°C. The crystals are washed door to door with water.

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. melting point is 218°C.

Example 22 (a) Methyl 5-(2-(2-fluoro-6-chlorophenyl)-acetyl) -2-Hydroxy-benzene acetate The main synthesis is carried out analogously to Example 19.

The synthesis of acetyl)-2-hydroxybenzene was carried out in the same manner as in Example 21. Ru.

NMR spectrum and elemental analysis data (1 Consistent with the structure of the title compound. The point is 240°C.

Example 23 2-Chloro-benzeneacetic acid 179. Thionyl chloride 10m, dimethylformamide (L5- and methylene chloride 150- are boiled for 6 hours. The solution is evaporated and The residue was dissolved in 50 methylene chloride containing 18 g of methyl 2-methoxy-benzene acetate. - dissolve in The resulting diluted solution was mixed with methane chloride containing 50 sd of lead chloride and 250 g of tyrene. Add dropwise. The solution was boiled for 24 hours, poured onto ice water, and diluted with chloroform. Extract, dry and treat with activated carbon ◇ Evaporate this chloroform solution and evaporate the residue. Recrystallize from tanol. The crystals were dissolved in 200 m of IM sodium hydroxide. Water was decomposed and diluted with water and ethanol 5o-d to about 300-d, then this solution was boiled. Acidify with acetic acid while boiling. After that, it is cooled and the crystals are distributed from house to house.

(b) 2-hydroxy-5-(2-(2-chlorophenyl)-a This synthesis is an example Perform the same procedure as in 3(b).

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. melting point is 230°C.

Example 24 The synthesis is carried out analogously to Example 16ib).

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. melting point is 212°C.

Example 25 This is carried out in the same manner as Example 23 (al).

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. melting point is 187°C.

This synthesis is carried out in the same manner as in Example 3(b).

The matching point 06 is 120°C.

Example 26 5-(2-chlorobenzoyl-2-hydroxy-benzene vinegar NMR spectra The molecular and elemental analysis data are consistent with the structure of the title compound. Melting point is 148℃ Chiru.

Example 27 5-benzoyl-2-methoxy-benzene vinegar a139t dimethylformamide 1 Dissolves in 50d. Dimethylformamide 50 containing sodium hydride xogt Cool the solution in water and add 30 g of methyl iodide little by little.

After about 6 hours the solution warms to room temperature. The last methyl iodide was added for another 16 hours. Add after cooling. Methanol is then added and the solution is poured over ice water-salts.

This is extracted with chloroform and the resulting solution is then evaporated. 50 pieces of residue Boil VJ in tanol IM sodium hydroxide solution for 2 hours. Pour the resulting solution o Put it in the mouth* and add it to the VC, and remove the magnesium chloride from this chloroform phase. Dehydrate and evaporate. Stir the residue with petroleum ether and decant the supernatant. The remaining layer is recrystallized from petroleum ether-benzene.

tb+ - Ben Lu - Hi'roxy αα - Ji Ruhen Tateotori Ward This synthesis is carried out in the same manner as in Example 3(b).

The NMR spectrum and elemental analysis data are consistent with the structure of the title compound. The melting point is The temperature is 207°C.

Example 28 5-(3-(λ4-dichloropheny/L/)-1-oxo-2-propenyl)- The main synthesis of 2- and doro-shibenzene acetic acid is carried out in the same manner as in Example xs (bl).

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. melting point The temperature is 232℃.

Example 29 5-3-4-1-methyl-ethyl-phenyl-1-oxo-2-pro penyl)-2-hydroxy-benzeneacetic acid This synthesis was carried out similarly to Example xs (bl). give

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. melting point is 228°C.

Example 30 5-(3-(4-methquinphenyl)-1-oxo-2-propenyl)-2-hyphenyl The main synthesis of droxy-benzeneacetic acid is carried out analogously to Example 16fb).

The NMR spectrum and elemental analysis data are consistent with the structure of the title compound. The point is 247°C.

Example 31 5-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-hydro Roxy-benzeneacetic acid The main synthesis is carried out in the same manner as in Example 16th).

The NMR spectrum and elemental analysis data are consistent with the structure of the M compound. Melting point ( d Ruru at 244℃.

Example 32 5-(4-7 cetylbenzoyl)-2-hydroxy-benzene vinegar rice 4-Acetylbenzoic acid 109. 7 ml thionyl chloride and 1 dimethylformamide Dissolve - in methylene chloride 100- and write for 3 hours for 5 hours. methylene chloride containing 2-methoxy-benzene acetate) IL39 50 rxt 100 MtK of methylene chloride mixed with aluminum chloride and suspended with 40 g of aluminum chloride was added dropwise. Add. The solution is boiled for 5 hours, poured onto ice water and extracted with chloroform.

The chloroform phase is evaporated and hydrolyzed in sodium hydroxide solution. this Acidify and extract with ethyl acetate. This ethyl acetate solution is condensed and the formed crystals are Go door to door. The crystals were dissolved in water-ethanol (3:1) and sodium hydroxide. let - Adjust to 7 and treat with activated carbon while heating gently. Add this solution to the acid Sexualize and cool. The product is separated and the crystals are isolated again in the same manner.

NMR spectrum and elemental analysis data are consistent with the structure of the title compound. melting point is 235c.

Example 33 2-hydroxy-5-(2-(4-carboxyphenyl)-1M sodium hydroxide 75-. Add 506 g of sodium bromine hydride in portions. this Boil the solution for 25 hours.

Add 15 ONt of 1M hydrochloric acid. The product is extracted with ethyl acetate.

The organic phase is dried and evaporated to dryness. Dissolve the residue in acetic acid 7s* and add sulfur 16- I can do it. The product is crystallized directly from the O bath.

This is dissolved in sodium V chloride and then acidified with formic acid. The melting point is 2 It's as high as 60 degrees Celsius.

Example 34 2-H)"0?C 5-(2-phenyl-1-ethynyl)-benzeneacetic acid 2-hydroxy/-5-(2-phenylacetyl)-benzeneacetic acid α68, water Sodium bromine α95g, tetrahydro7ran 20- and 1M sodium hydroxide Reflux 20 m of aluminum for 1 hour. Shake and mix this solution with 100- ether. do. The aqueous phase is acidified to 3°C and extracted 3 times with 50°C of ether. This etheric phase Combine, dehydrate and evaporate to dryness.

The residue is dissolved in 16 d of acetic acid and 4 d of concentrated sulfuric acid. Boil this solution in the dark for 15 minutes, then add water Pour on top and extract with ether, then evaporate this ether phase.

This residue is dissolved in IM sodium hydroxide. When hydrochloric acid is added, the product crystallizes. It's coming.

NMR spectrum and elemental analysis data are consistent with the thin structure of the title compound6 The melting point is 202°C.

Example 35 5-2-methyl-1-oxo-3-phenyl-2-gropenyl-2-hydro xy-benzeneacetic acid Methyl 5-propanoyl-2-hydroxy-benzeneacetic acid 119, benzalde 6 g of hydride 1α, 150 mt of ethanol and 50 mt of ether saturated with hydrogen arsenide chloride Reflux the mixture for 5 days. The solution is poured onto water and extracted with ethyl acetate. This acetic acid Evaporate the ethyl and hydroxylate the residue) Hydrolyze in IJum solution. - to 7 Adjust and wash this solution with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. put out The ethyl acetate was evaporated and the residue was leached with dichloroethane and 2-butane Recrystallize from non/L2-dichloroethane.

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is 192°C.

Example 36 This synthesis is similar to Example 16(b).

NMRM spectrum and elemental analysis data are consistent with the title compound. melting point is 235°C.

Meiho Example 37 5-(3-(4-cyanophenyl)-1-oxo-2-propenyl di-2-hydride The main synthesis of roxy-benzene acetic acid was carried out in the same manner as in Example x6(b).

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is 249°C.

Example 38 5-("3-(4-)lifluoromethylphenyl)-1-oxo-2 synthesis Fi Example 16 (conducted in the same manner as in BL).

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is as high as 260℃.

Example 39 This synthesis is carried out in the same manner as in Example 1s(b>).

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is 210°C.

Implementation example 40 5-(3-(λ4-dimethoxyphenyl)-1-oxo-2-propenyl2 -Hydroxy-Pen’r! 7 Vinegar d Main synthesis was carried out in the same manner as in Example 16th). Ru.

NMRM spectrum and elemental analysis data are consistent with the structure of the title compound @ melting point is 225°C Example 41 This synthesis was carried out in the same manner as in Example 10. The NMRM spectrum and elemental analysis data were ta is consistent with the structure of the title compound. The melting point is 149°C.

Example 42 5-4-nitrobenzoyl-2-hydroxy-benzoic acid This synthesis is carried out in the same manner as in Example 10.

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point is 213°C.

Example 43 5-4-Methylbenzoyl-2-hydroxy-benzene The light will come in the same way as 0.

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point IF is 218°C.

Example 44 This synthesis is carried out in the same manner as in Example 10. Dissolve the product in chloroform and add water Mix with At the same time, add sodium hydroxide and adjust to 7.2. Separate the phases Lyophilize the aqueous phase.

NMRM spectra and elemental analysis data are consistent with the structure of the title compound. melting point Chills at about 170°C 2 Example 45 This synthesis is carried out in the same manner as in Example 10.

The NM concentration spectrum and elemental analysis data are consistent with the structure of the title compound. melting point is 186°C.

Example 46 5-benzoyl-2-hydroxy-6-methylpenze/acetic acid Main synthesis Example 1 Execute in the same manner as 0.

N) JR spectrum and elemental analysis data are consistent with the structure of the titled ornament. Melt The point is 212°C.

Meiji Example 47 Inhibition of 15-hydroxy-prostaglandin dehydrogenase 15-hydroxy-prostaglandin dehydrogenase As an inhibitor of sea-glostaglandin dehydrogenase (PGDH) The effect of the compound is shown by in vitro measurements. holt (oult) and more (Moore) Vt, <British Journal on-77-Makologie -: Br1tish Journal of Pharmacology 61 (1977), p. a1s) from which cells had been removed (Human placenta) PGDH-containing) and radioactive grosstaglandin F, (PGF) were incubated together. Bate. After an appropriate incubation time, extract the broth-tagged 2-ginsin. Branched by chromatography. And the amount of P G F * that has not changed is 1 generation Compare it with the amount of praise. Varying the amount of inhibitor added and performing experiments without adding inhibitor. Concentrations of those compounds at which 50% inhibition of degradation is achieved compared to control experiments The inhibitory effect is evaluated by measuring (ICIII). lOμM or less A substance that inhibits PGDH050% at the following concentrations is very good. ) considered as a harmful agent. Inhibits 50% of PGDH at degrees between 10 and 100 μM A good inhibitor is one that does so. The compound cannot be said to be good ( 1ess good). This is a throw at 5il. In certain cases, ri may have other properties such as low toxicity or pharmacokinetic properties distinct from F'i loading. It is often found that the characteristics are offset by important characteristics.

The ICIII values of a number of uninvented compounds are listed below.◎For comparison, The known PGDH effective inhibitor described in European Patent Publication No. 21229 Mei-Bara, 5-phere The IC1° value for nilazo-2-hydroxybenzeneacetic acid is also listed. novelization Compound i-j: Despite its PGDH inhibitory effect, its toxicity is relatively low It is. In a number of the compounds of the invention that are sparing with respect to toxicity, the intraperitoneal When measured by internal administration, the acute toxicity was 9 in 1300 to 728 Da/. be.

International 1A section center bw-m,,=　a□+--PCT/SEI]5100020mAMkPcT/ SEa5100020

Claims (11)

[Claims] 1. The structure below ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) [In the formula, R1 and R2 are hydrogen atoms or Lower alkyl, preferably R2 represents a hydrogen atom: R3 represents a hydrogen atom, lower alkyl or optionally substituted phenyl: R4R5 and R6 are hydrogen atoms, halogen, lower alkyl, lower alkoxy, sia nitro, carboxy or nitro, and at least one of the groups R4 to R6 is It is a hydrogen atom: R7 to R11 are hydrogen atoms, halogen, cyano, lower alkali Kyl, trifluoromethyl, lower alkoxy, hydroxy, lower acyl, lower acyl rukoxycarbonyl, N,N-di-lower alkylaminocarbonyl or N,N-lower represents alkylene-aminocarbonyl, and R6 to R10 can also be carboxy. possible, at least two after R1 to R11 are always hydrogen atoms, preferably R7 and R11 are hydrogen atoms, halogen, cyano, lower alkyl, trifluoro Methyl, lower alkoxy, hydroxy or lower acyl: A is -CO-, -CH2-CO-, -CH=CH-, -CH=CH-CO- or Indicates a corresponding group in which the hydrogen atom in the above is substituted with a lower alkyl group: or the compound is a salt of the compound if it contains at least one carboxyl group; or When R1 is H, it is the corresponding lactone] An arylacetic acid derivative represented by 2. According to claim 1, R2 is a hydrogen atom or a corresponding carboxylate salt. arylacetic acid derivatives of. 3. The aryl according to claim 1 or 2, wherein R3 to R5 are hydrogen atoms. Acetic acid derivative. 4. Claims 1 to 5, wherein R1 is a hydrogen atom and is a lactone of the corresponding acid. The arylacetic acid derivative according to any one of Item 3. 5. Claim No. 1, wherein at least one of R8R9 and R10 is carboxy. The arylacetic acid derivative according to any one of items 1 to 4. 6. Claim 1 does not include R4, R5, R6, R7 and R11 are hydrogen atoms. The arylacetic acid derivative according to any one of Item 5. 7. The aryl according to any one of claims 1 to 6, wherein A is -CO- Acetic acid derivative. 8. According to any one of claims 1 to 6, A is -CH=CH- arylacetic acid derivatives of. 9. A is -CH2-CO- according to any one of claims 1 to 6. aryl acetic acid derivatives. 10. Any one of claims 1 to 6, wherein A is -CH=CH-CO- The aryl acetic acid derivative described in Crab. 11. Therapeutically effective compounds according to any of claims 1 to 10 A pharmaceutical composition comprising: